Biomedical subjects
Publications and source records attributed to Stewart P Thompson.
A detailed NMR study of the thiopeptide amythiamicin D establishes its solution conformation and the presence of a single intramolecular hydrogen bond involving NH13 and O28, and also provides the first evidence for self-association of thiopeptides in solution.
The thiopeptide (or thiostrepton) antibiotics are a class of sulfur containing highly modified cyclic peptides with interesting biological properties, including reported activity against MRSA and malaria. Described herein is the total synthesis of the thiopeptide natural product amythiamicin D, which utilizes a biosynthesis-inspired hetero-Diels-Alder route to the pyridine core of the antibiotic as a key step. Preliminary studies using a range of serine-derived 1-ethoxy-2-azadienes established that hetero-Diels-Alder reaction with N-acetylenamines proceeded efficiently under microwave irradiation to give 2,3,6-trisubstituted pyridines. The thiazole building blocks of the antibiotic were obtained by either classical Hantzsch reactions or by dirhodium(II)-catalyzed chemoselective carbene N-H insertion followed by thionation, and were combined to give the bis-thiazole that forms the left-hand fragment of the antibiotic. The key Diels-Alder reaction of a tris-thiazolyl azadiene with benzyl 2-(1-acetylaminoethenyl)thiazole-4-carboxylate gave the core tetrathiazolyl pyridine, which was elaborated into the natural product by successive incorporation of glycine and bis-thiazole fragments followed by macrocyclization.
[reaction: see text] The treatment of chiral trans-disubstituted and trisubstituted 2,3-epoxy-1-bromides with an excess of dimethylsulfonium methylide 1 affords the corresponding 1,3-butadien-2-ylmethanols in good to excellent yields via a double one-carbon homologation.
The first total synthesis of the thiopeptide antibiotic amythiamicin D is described.
Reaction of serine derived 1-alkoxy-2-azadienes with dehydroalanine derived dienophiles results in Diels-Alder reaction and aromatisation to give 2,3,6-trisubstituted pyridines, thereby establishing the viability of the proposed biosynthetic route to the pyridine ring of the thiopeptide antibiotics originally proposed by Bycroft and Gowland.